Mid- and late-life lifestyle activities as main drivers of general and domain-specific cognitive reserve in individuals with Parkinson’s disease: cross-sectional and longitudinal evidence from the LANDSCAPE study

Background Cognitive reserve (CR) is considered a protective factor for cognitive function and may explain interindividual differences of cognitive performance given similar levels of neurodegeneration, e.g., in Alzheimer´s disease. Recent evidence suggests that CR is also relevant in Parkinson’s disease (PD). Objective We aimed to explore the role of life-stage specific CR for overall cognition and specific cognitive domains cross-sectionally and longitudinally in PD. Methods The cross-sectional analysis with data from the DEMPARK/LANDSCAPE study included 81 individuals without cognitive impairment (PD-N) and 87 individuals with mild cognitive impairment (PD-MCI). Longitudinal data covered 4 years with over 500 observations. CR was operationalized with the Lifetime of Experiences Questionnaire (LEQ), capturing the complexity of lifestyle activities across distinct life-stages. Cognition was assessed using a comprehensive neuropsychological test battery. Results Higher LEQ scores, particularly from mid- and late-life, were observed in PD-N compared to PD-MCI [F(1,153) = 4.609, p = .033, ηp2 = 0.029]. They were significantly associated with better cognitive performance (0.200 ≤ β ≤ 0.292). Longitudinally, linear mixed effect models (0.236 ≤ marginal R2 ≤ 0.441) revealed that LEQ scores were positively related to cognitive performance independent of time. However, the decline in overall cognition and memory over time was slightly more pronounced with higher LEQ scores. Conclusions This study emphasizes the association between complex lifestyle activities and cognition in PD. Data indicate that while CR might be related to a delay of cognitive decline, individuals with high CR may experience a more pronounced drop in overall cognition and memory. Future studies will have to replicate these findings, particularly regarding domain-specific effects and considering reverse causal mechanisms. Supplementary Information The online version contains supplementary material available at 10.1007/s00415-024-12484-0.


Mid-and late-life lifestyle activities as main drivers of general and domain-specific cognitive reserve in individuals with
MCST Non-perseverative errors X Nelson [4] MCST Perseverative errors X Nelson [4] Digit Span Backward WMS-R

Composition of the Lifetime of Experiences Questionnaire (Sub-)Scores
The contribution of complex lifestyle activities in young adulthood, mid-life and late-life either specific or non-specific for the corresponding life-stage to the LEQ total score was analyzed in a 3x2 ANOVA with life-stage (young adulthood vs. mid-life vs. late-life) and specificity (specific vs. non-specific) as within-subjects factors.Post-hoc tests were Bonferroni-adjusted.
There was a significant main effect of life-stage with a medium effect size between the non-specific scores of young adulthood and mid-life and between young adulthood and late-life.For young adulthood, there was no significant difference between the normalized specific score and the non-specific score, indicating an equal contribution of lifestage specific and non-specific activities to total CR.For both mid-life and late-life there were significant differences between the normalized specific score and the non-specific score, however, in opposite directions: For mid-life, the specific score (20.02±10.03)was significantly higher than the non-specific score (18.05±4.08),indicating a stronger contribution of life-stage specific activities (i.e., occupational history) compared to unspecific activities.For late-life, the non-specific score (19.15±6.25)was significantly higher than the specific score (14.58±3.66),indicating a stronger influence of non-life-stage-specific activities (e.g., travel, visiting family, playing musical instruments, doing arts, physical activities, reading, and speaking a foreign language) compared to life-stage specific social and intellectual activities.

Life-stage specific vs. non-specific associations with cognitive performance over time
To get a more detailed understanding of life-stage specific vs. non-specific associations with cognitive performance over time, we built a bivariate correlation matrix of all LEQ subscores (life-stage x specificity) (life-stage x specificity) with cross-sectional cognitive performance at LEQ baseline as well as the difference scores of cognitive performance per year follow-up compared to the LEQ baseline (Supplementary Figure S2).The strongest and most consistent correlations for cross-sectional cognitive performance were found for non-specific mid-life lifestyle activities and specific late-life lifestyle activities.The bivariate association with cognitive change over time is weaker, with a tendency for specific young adulthood proxies of CR (which is mainly determined by education in the LEQ) showing stronger negative associations with cognitive performance.

Details on the construction
of life-stage specific subscores of the Lifetime of Experiences Questionnaire By equally weighting specific and non-specific scores from each of the three life-stages, three subscores are constructed: young adulthood, mid-life, and late-life.Each subscore combines both the specific and non-specific scores, with each subscore contributing 33.3% to the overall LEQ total score.The scoring for the present analyses was based on the recently revised German LEQ version (LEQ-D) of Roeske, et al. [9].To ensure equal weighting of the specific and nonspecific scores of each life-stage, normalization factors were applied to adjust for the different value ranges of the life-stage specific LEQ scores.Unlike Valenzuela and Sachdev [10], where these factors are based on the group mean, the normalization factors in the present study were based on the range of item values for each life stage, resulting in sample-independent values.The normalization factors were determined by calculating the quotient of the maximum unspecific score and the maximum specific score.The normalization factor for young adulthood was 1.03 (35/34), for mid-life 0.71 (35/49), and for late-life 0.83 (35/42).The specific scores of each life-stage were then corrected with their corresponding normalization factor before being added to the unspecific score of each life-stage, resulting in the equal weighting of the specific and non-specific score for each life-stage.

Fig. S1
Fig. S1 Lifetime of Experience Questionnaire scores by contributing life-stage and specificity a. Composition of the baseline scores of the Lifetime of Experiences Questionnaire (LEQ) by life-stage (young adulthood, midlife, late-life) and specificity (specific vs. non-specific) regarding the lifestyle activities for the corresponding life-stage.b.Comparison of the LEQ scores by life-stage and specificity.Dots and squares represent individual LEQ subscores, the groupwise boxplots visualize the within-group median, the hinges represent the corresponding first and the third quartile, and the whiskers are 1.5 * the inter-quartile range.Lines indicate significant (p < .05)Bonferroni-adjusted pairwise comparisons for the main effect of life-stage (black) and the interaction of life-stage and specificity (grey).

Fig. S2
Fig. S2 Bivariate Pearson correlation matrix of demographic and clinical variables and the Lifetime of Experiences Questionnaire subscores with cognitive performance at baseline and longitudinal difference scores The color spectrum represents the Peason correlation coefficient from min.-0.5 (dark red) to max.0.5 (dark blue).Crosses indicate non-significant (p≥.05) correlations.LEDD, Levodopa Equivalent Daily Dose; LEQ, Lifetime of Experiences Questionnaire.

Parkinson's disease: Cross-sectional and longitudinal evidence from the LANDSCAPE study Supplementary MaterialTable S1 .
Cognitive Tests used in the DEMPRAK/LANDSCAPE Cohort and Their Relevance for the Diagnosis of Parkinson's Disease Mild Cognitive Impairment

Table S2 .
Sociodemographic, clinical, and cognitive characteristics of the DEMPARK/LANDSCAPE sample: completed study vs. lost to attrition.Data are mean and standard deviation unless indicated otherwise.p-values of independent sample t-tests or c 2 -tests between individuals with PD-N and PD-MCI & PDD are presented.CERAD-Plus Total Score, Consortium to establish a Registry